The present invention relates to novel compositions and methods for inhibiting inflammatory responses associated with autoimmune diseases. In particular, it relates to vaccination with peptides from the extracellular regions of chemokine receptor molecules.
Chemokines constitute a family of small molecular weight cytokines that are produced in inflammation and regulate leukocyte recruitment. These molecules are ligands for seven transmembrane G protein linked receptors that induce a signaling cascade costimulation for T cell activation in addition to participating in transendothelial migration of leukocytes (Oppenheim et al. Ann. Rev. Immunol. 9:617-648 (1991), Premback et al. Nat. Med. 2:1174-1178 (1996)). Two subfamilies of chemokines, referred to as CC and CXC, have been discovered. CC and CXC chemokines are distinct from each other in their N terminal amino acid sequence which starts either with cysteine-cysteine or cysteine-X-cysteine where X is typically another L-amino acid. They are also distinct in their binding pattern to their receptors. For example, the CC chemokines bind to CC receptors and not to CXC receptors and vice versa.
Different chemokines regulate the trafficking of distinct populations of hemopoietic cells by activating specific 7-transmembrane receptors expressed by these cells (Baggiolini et al. Adv. Immunol. 55:97-179 (1994); Gerard et al. Curr. Opin. Immunol. 6:140-145 (1994)). Recent publications indicate that the Th1 and Th2 subsets of regulatory T cells are uniquely characterized by the chemokine receptors CXCR3 and CCR3, respectively (Sallusto, et al. J. Exp. Med. 187:875-883 (1998); Bonecchi, et al. J. Exp. Med. 187:129-134 (1998); Qin, et al. J. Clin Invest. 101:746-754 (1998)). Several studies have correlated the expression of three specific chemokines, IP-10, RANTES, and MCP-1, produced by astrocytes in the CNS with the presence of inflammatory infiltration within this tissue during the early phase of EAE (Ransohoff, et al. FASEB J. 7:592-600 (1993); Glabinski et al. Am. J. Pathol. 150:617-630 (1995) Godiska, et al. J. Neuroimmunol. 58:167-176 (1995); and Eng et al. Neurchem. Res. 21:511-525 (1996)). While all three chemokines have been shown to be capable of recruiting T lymphocytes in certain experimental models, IP-10 has been demonstrated to be specific for this lineage of hemopoietic cells (Taub et al. J. Exp. Med. 177:1809-1814 (1993)); Carr, etal. Proc. Natl. Acad. Sci. USA 91:3652-3656 (1994); and Farber, J. Leukoc. Biol. 61:246-257 (1997). MBP-immunized rats intrathecaly infused with an antisense phosphorothioate oligonucleotide to crg-2 (the murine homologue of human IP-10) show reduced disease clinical score of EAE (Wojcik, et al. J. Pharmacol. Exp. Ther. 278:404-410 (1996)).
In addition, higher expression of some of the chemokine receptors such as CXCR3 on IL2 activated human T lymphocytes and not on resting T lymphocytes has been demonstrated (Loetscher et al. J. Exp. Med. 184:963-969 (1996)).
Multiple sclerosis (MS) is a T cell-dependent autoimmune disease caused by localized demyelination in the central nervous system (CNS), with only limited therapeutic options available to patients. Extensive investigation has indicated that these autoreactive T lymphocytes frequently, though not always, express the Th1 phenotype of high level production of IFNg, IL-2 and TNFa, with little to no IL-4, IL-5 and IL-10.
Current therapeutics for autoimmune diseases, such as MS, involve the use of antiinflammatory agents or general immunosuppressants. Prior art methods for controlling autoimmune disease fail to provide a simple self-mediated method for specifically eliminating inflammatory responses mediated by chemokines associated with the autoimmune responses. The present invention addresses these and other needs.